A nonapeptide having the sequence L-Trp-L-Ala-Gly-Gly-L-Asp-L-Ala-L-Ser-Gly-L-Glu (MW=849), hereinafter referred to as DSIP (Delta-Sleep-Inducing Peptide) was isolated in the period 1971-1977 as the humoral sleep factor from the blood of rabbits, purified and characterized. Its structure was also finally elucidated (Pflugers Arch. 369, 99-101, 1977). Biological tests carried out using synthetic DSIP gave identical results in comparison with natural DSIP isolated from rabbit blood when administered intra-cerebral-ventricularly in rabbits (Experientia 33, 548, 1977). Intra-cerebral-ventricular doses of 6 nMol DSIP/kg induced a physiological effect in rabbits which on an EEG manifested itself as being equivalent to the phenomena found during natural orthodox deep sleep (Proc. Natl. Acad. Sci. USA 74, 1282-1286, 1977). Synthetically prepared DSIP was also active following intravenous administration of 30 nMol/kg in cats and rats, whereby the EEG recordings and also the passive behavioural tests showed a significant improvement in deep and paradoxal sleep. The administration of synthetic DSIP by means of an arterial perfusion on isolated rat heads also gave EEG readings which were sleep equivalent. In animal trails, methods of application which may also be used in human medicine also resulted in the induction of a natural state of sleep.
It has, however, been shown in a series of experiments, that the induction of sleep following the administration of DSIP, results in an all or nothing effect when the dosage varies by only .+-.20 nMol/kg body weight, that is, only the exact dosage of the correct quantity of DSIP achieves the desired effect. Furthermore, it has been found that intravenous administration requires a dosage of 6 nMol/kg which is substantially higher than that required for intra-cerebral-ventricular administration for the induction of sleep and finally, if administration is carried out by the intravenous route, there is a delay before the induction of sleep.
These differences in activity following the two types of application are not surprising, since oligopeptides of the DSIP type are known from experience to undergo rapid enzymatic degradation on intravenous (sub- or percutaneous) application and in addition do not easily penetrate the blood brain barrier.